The present invention is concerned with novel 1,2-annelated quinoline derivatives, the preparation thereof, pharmaceutical compositions comprising said novel compounds and the use of these compounds as a medicine as well as methods of treatment by administering said compounds.
Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer. A particular group of oncogenes is known as ras which have been identified in mammals, birds, insects, mollusks, plants, fungi and yeasts. The family of mammalian ras oncogenes consists of three major members (xe2x80x9cisoformsxe2x80x9d): H-ras, K-ras and N-ras oncogenes. These ras oncogenes code for highly related proteins generically known as p21ras. Once attached to plasma membranes, the mutant or oncogenic forms of p21ras will provide a signal for the transformation and uncontrolled growth of malignant tumor cells. To acquire this transforming potential, the precursor of the p21ras oncoprotein must undergo an enzymatically catalyzed farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Therefore, inhibitors of the enzymes that catalyzes this modification, i.e. farnesyl transferase, will prevent the membrane attachment of p21ras and block the aberrant growth of ras-transformed tumors. Hence, it is generally accepted in the art that farnesyl transferase inhibitors can be very useful as anticancer agents for tumors in which ras contributes to transformation.
The K-ras B isoform has been observed to be the dominant isoform which is mutated in human cancers, particular in colon (50% incidence) and pancreatic (90% incidence) cancers. However, it was also found that ras protein activation in the K-ras B isoform transformed cancers is resistant to inhibition of farnesyl transferase. The isoform confers resistance to farnesyl transferase inhibitors, but makes this isoform also substrate for geranylgeranyl transferase I. Therefore, inhibitors of geranylgeranyl transferase may inhibit the aberrant growth of K-ras transformed tumors which are resistant to famesyl transferase inhibitors.
Since mutated oncogenic forms of ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, vol 260, 1834-1837, 1993), it has been suggested that farnesyl tranferase inhibitors can be very useful against these types of cancer.
In EP-0,371,564 there are described (1H-azol-1-ylmethyl) substituted quinoline and quinolinone derivatives which suppress the plasma elimination of retinoic acids. Some of these compounds also have the ability to inhibit the formation of androgens from progestines and/or inhibit the action of the aromatase enzyme complex.
In WO 97/16443, WO 97/21701, WO 98/40383 and WO 98/49157, there are described 2-quinolone derivatives which exhibit farnesyl transferase inhibiting activity.
Unexpectedly, it has been found that the present novel 1,2-annelated quinoline compounds, bearing a nitrogen- or carbon-linked imidazole, show farnesyl protein transferase and geranylgeranyl transferase inhibiting activity.
The present invention concerns compounds of formula 
or the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
xe2x95x90X1xe2x80x94X2xe2x80x94X3xe2x80x94 is a trivalent radical of formula
xe2x95x90Nxe2x80x94CR6xe2x95x90CR7xe2x80x94 (x-1),
xe2x95x90Nxe2x80x94Nxe2x95x90CR6xe2x80x94 (x-2),
xe2x95x90Nxe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 (x-3),
xe2x95x90Nxe2x80x94Nxe2x95x90Nxe2x80x94 (x4),
xe2x95x90Nxe2x80x94CR6xe2x95x90Nxe2x80x94 (x-5),
xe2x95x90CR6xe2x80x94CR7xe2x95x90CR8xe2x80x94 (x-6),
xe2x95x90CR6xe2x80x94Nxe2x95x90CR7xe2x80x94 (x-7),
xe2x95x90CR6xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 (x-8), or
xe2x95x90CR6xe2x80x94Nxe2x95x90Nxe2x80x94 (x-9);
xe2x80x83wherein each R6, R7 and R8 are independently hydrogen, C1-4alkyl, hydroxy, C1-4alkyloxy, aryloxy, C1-4alkyloxycarbonyl, hydroxyC1-4alkyl, C1-4alkyloxyC1-4alkyl, mono- or di(C1-4alkyl)aminoC1-4alkyl, cyano, amino, thio, C1-4alkylthio, arylthio or aryl;
 greater than Y1xe2x80x94Y2xe2x80x94 is a trivalent radical of formula
 greater than CHxe2x80x94CHR9xe2x80x94 (y-1),
 greater than Cxe2x95x90Nxe2x80x94 (y-2),
 greater than CHxe2x80x94NR9xe2x80x94 (y-3), or
 greater than Cxe2x95x90CR9xe2x80x94 (y-4);
xe2x80x83wherein each R9 independently is hydrogen, halo, halocarbonyl, aminocarbonyl, hydroxyC1-4alkyl, cyano, carboxyl, C1-4alkyl, C1-4alkyloxy, C1-4alkyloxyC1-4alkyl, C1-4alkyloxycarbonyl, mono- or di(C1-4alkyl)amino, mono- or di(C1-4alkyl)aminoC1-4alkyl, aryl;
r and s are each independently 0, 1, 2, 3, 4 or 5;
t is 0, 1, 2 or 3;
each R1 and R2 are independently hydroxy, halo, cyano, C1-6alkyl trihalomethyl, trihalomethoxy, C2-6alkenyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkylthio, C1-6alkyloxyC1-6alkyloxy, C1-6alkyloxycarbonyl, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)amino, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, aryl, arylC1-6alkyl, aryloxy or arylC1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl, aminocarbonyl, aminoC1-6alkyl, mono- or di(C1-6alkyl)aminocarbonyl, mono- or di(C1-6alkyl)aminoC1-6alkyl; or
two R1 or R2 substituents adjacent to one another on the phenyl ring may independently form together a bivalent radical of formula
xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94 (a-1),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94 (a-2),
xe2x80x94Oxe2x95x90CHxe2x95x90CHxe2x80x94 (a-3),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94 (a-4),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 (a-5), or
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 (a-6);
R3 is hydrogen, halo, C1-6alkyl, cyano, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, aminoC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl, aminocarbonylC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, C1-6alkylcarbonylC1-6alkyl, C1-6alkyloxycarbonyl, aryl, arylC1-6alkyloxyC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl;
or a radical of formula
xe2x80x94Oxe2x80x94R10 (b-1),
xe2x80x94Sxe2x80x94R10 (b-2),
xe2x80x94NR11R12 (b-3),
wherein R10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, aryl, arylC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical of formula -Alk-OR3 or -Alkxe2x80x94NR14R15;
R11 is hydrogen, C1-6alkyl, aryl or arylC1-6alkyl;
R12 is hydrogen, C1-6alkyl, aryl, hydroxy, amino, C1-6alkyloxy, C1-6alkylcarbonylC1-6alkyl, arylC1-6alkyl, C1-6alkylcarbonylamino, mono- or di(C1-6alkyl)amino, C1-6alkylcarbonyl, aminocarbonyl, arylcarbonyl, haloC1-6alkylcarbonyl, arylC1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkyloxyC1-6alkylcarbonyl, mono- or di(C1-6alkyl)aminocarbonyl wherein the alkyl moiety may optionally be substituted by one or more substituents independently selected from aryl or C1-3alkyloxycarbonyl, aminocarbonylcarbonyl, mono- or di(C1-6alkyl)aminoC1-6alkylcarbonyl, or a radical or formula -Alk-OR13 or -Alkxe2x80x94NR14R15;
xe2x80x83wherein Alk is C1-6alkanediyl;
R13 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxyC1-6alkyl, aryl or arylC1-6alkyl;
R14 is hydrogen, C1-6alkyl, aryl or arylC1-6alkyl;
R15 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, aryl or arylC1-6alkyl;
R4 is a radical of formula 
wherein R16 is hydrogen, halo, aryl, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1 6alkylthio, amino, mono- or di(C1-4alkyl)amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylthioC1-6alkyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;
R16 may also be bound to one of the nitrogen atoms in the imidazole ring of formula (c-1) or (c-2), in which case the meaning of R16 when bound to the nitrogen is limited to hydrogen, aryl, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;
R17 is hydrogen, C1-6alkyl, C1-6alkyloxyC1-6alkyl, arylC1-6alkyl, trifluoromethyl or di(C1-4alkyl)aminosulfonyl;
R5 is C1-6alkyl , C1-6alkyloxy or halo;
aryl is phenyl, naphthalenyl or phenyl substituted with 1 or more substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl.
A special group of compounds contains those compounds of formula (I) wherein
each R1 and R2 are independently hydroxy, halo, cyano, C1-6alkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkylthio, C1-6alkyloxyC1-6alkyloxy, C1-6alkyloxycarbonyl, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)amino, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, aryl, arylC1-6alkyl, aryloxy or arylC1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl; or
two R1 or R2 substituents adjacent to one another on the phenyl ring may independently form together a bivalent radical of formula
xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94 (a-1),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94 (a-2),
xe2x80x94Oxe2x95x90CHxe2x95x90CHxe2x80x94 (a-3),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94 (a-4),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 (a-5), or
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 (a-6);
R16 is hydrogen, halo, aryl, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, mono- or di(C1-4alkyl)amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylthioC1-6alkyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;
R16 may also be bound to one of the nitrogen atoms in the imidazole ring of formula (c-1), in which case the meaning of R16 when bound to the nitrogen is limited to hydrogen, aryl, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;
R17 is hydrogen, C1-6alkyl, trifluoromethyl or di(C1-4alkyl)aminosulfonyl.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C1-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, e.g. methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C1-6alkyl includes C1-4alkyl and the higher homologues thereof having 5 to 6 carbon atoms such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; C1-6alkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof; C2-6alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like. The term xe2x80x9cS(O)xe2x80x9d refers to a sulfoxide and xe2x80x9cS(O)2xe2x80x9d to a sulfon.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The compounds of formula (I) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating said base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
The term acid addition salts also comprises the hydrates and the solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The term stereochemically isomeric forms of compounds of formula (I), as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of formula (I) both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
Whenever used hereinafter, the term xe2x80x9ccompounds of formula (I)xe2x80x9d is meant to include also the pharmaceutically acceptable acid addition salts and all stereoisomeric forms.
A group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply:
xe2x95x90X1xe2x80x94X2xe2x80x94X3 is a trivalent radical of formula (x-1), (x-2), (x-3), (x4) or (x-9) wherein each R6 independently is hydrogen, C1-4alkyl, C1-4alkyloxycarbonyl, amino or aryl and R7 is hydrogen;
 greater than Y1xe2x80x94Y2xe2x80x94 is a trivalent radical of formula (y-1), (y-2), (y-3), or (y-4) wherein each R9 independently is hydrogen, halo, carboxyl, C1-4alkyl or C1-4alkyloxycarbonyl;
r is 0, 1 or 2;
s is 0 or 1;
t is 0;
R1 is halo, C1-6alkyl or two R1 substituents ortho to one another on the phenyl ring may independently form together a bivalent radical of formula (a-1);
R2 is halo;
R3 is halo or a radical of formula (b-1) or (b-3) wherein
R10 is hydrogen or a radical of formula -Alk-OR13.
R11 is hydrogen;
R12 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxy, C1-6alkyloxy or mono- or
di(C1-6alkyl)aminoC1-6alkylcarbonyl;
Alk is C1-6alkanediyl and R13 is hydrogen;
R4 is a radical of formula (c-1) or (c-2) wherein
R16 is hydrogen, halo or mono- or di(C1-4alkyl)amino;
R17 is hydrogen or C1-6alkyl;
aryl is phenyl.
A particular group of compounds consists of those compounds of formula (I) wherein xe2x95x90X1xe2x80x94X2xe2x80x94X3 is a trivalent radical of formula (x-1), (x-2), (x-3) or (x-9),  greater than Y1xe2x80x94Y2 is a trivalent radical of formula (y-2), (y-3) or (y-4), r is 0 or 1, s is 1, t is 0, R1 is halo, C1-4)alkyl or forms a bivalent radical of formula (a-1), R2 is halo or C1-4alkyl, R is hydrogen or a radical of formula (b-1) or (b-3), R4 is a radical of formula (c-1) or (c-2), R6 is hydrogen, C1-4alkyl or phenyl, R7 is hydrogen, R9 is hydrogen or C1-4alkyl, R10 is hydrogen or -Alk-OR13, R11 is hydrogen and R12 is hydrogen or C1-6alkylcarbonyl and R13 is hydrogen;
Preferred compounds are those compounds of formula (I) wherein xe2x95x90X1xe2x80x94X2xe2x80x94X3 is a trivalent radical of formula (x-1),  greater than Y1xe2x80x94Y2 is a trivalent radical of formula (y-4), r is 0 or 1, s is 1, t is 0, R1 is halo, preferably chloro and most preferably 3-chloro, R2 is halo, preferably 4-chloro or 4-fluoro, R3 is hydrogen or a radical of formula (b-1) or (b-3), R4 is a radical of formula (c-1) or (c-2), R6 is hydrogen, R7 is hydrogen, R9 is hydrogen, R10 is hydrogen, R11 is hydrogen and R12 is hydrogen;
Other preferred compounds are those compounds of formula (I) wherein xe2x95x90X1xe2x80x94X2xe2x80x94X3 is a trivalent radical of formula (x-2) or (x-3),  greater than Y1xe2x80x94Y2 is a trivalent radical of formula (y-2), (y-3) or (y-4), r and s are 1, t is 0, R1 is halo, preferably chloro, and most preferably 3-chloro or R1 is C1-4alkyl, preferably 3-methyl, R2 is halo, preferably chloro, and most preferably 4-chloro, R3 is a radical of formula (b-1) or (b-3), R4 is a radical of formula (c-2), R6 is C1-4alkyl, R9 is hydrogen, R10 and R11 are hydrogen and R12 is hydrogen or hydroxy;
The most preferred compounds of formula (I) are 7-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]-5-phenylimidazo[1,2-a]quinoline; xcex1-(4-chlorophenyl)-xcex1-(1-methyl-1H-imidazol-5-yl)-5-phenylimidazo[1,2-]aquinoline-7-methanol; 5-(3-chlorophenyl)-xcex1-(4-chlorophenyl)-xcex1-(1-methyl-1H-imidazol-5-yl)-imidazol[1,2-a]quinoline-7-methanol; 5-(3-chlorophenyl)-xcex1-(4-chlorophenyl)-xcex1-(1-methyl-1H-imidazol-5-yl)imidazol[1,2-a]quinoline-7-methanamine; 5-(3-chlorophenyl)-xcex1-(4-chlorophenyl)-xcex1-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinoline-7-methanamine; 5-(3-chlorophenyl)-xcex1-(4-chlorophenyl)-1-methyl-xcex1-(1-methyl-1H-imidazol-5-yl)-1,2,4-triazolo[4,3-a]quinoline-7-methanol; 5-(3-chlorophenyl)-xcex1-(4- chlorophenyl)-xcex1-(1-methyl-1-imidazol-5-yl)tetrazolo[1,5-a]quinoline-7-methanamine; 5-(3-chlorophenyl)-xcex1-(4-chlorophenyl)-xcex1-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanol; 5-(3-chlorophenyl)-xcex1-(4-chlorophenyl)-4,5-dihydro-xcex1-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanol; 5-(3-chlorophenyl)-xcex1-(4-chlorophenyl)-xcex1-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanamine; 5-(3-chlorophenyl)-xcex1-(4-chlorophenyl)-N-hydroxy-xcex1-(1-methyl-1H-imidazol-5-yl)tetrahydro[1,5-a]quinoline-7-methanamine; xcex1-(4-chlorophenyl)-xcex1-(1-methyl-1H-imidazol-5-yl)-5-(3-methylphenyl)tetrazolo[1,5-a]quinoline-7-methanamine; the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof.
The compounds of formula (I) wherein xe2x95x90X1xe2x80x94X2xe2x80x94X3 is a trivalent radical of formula (x-1) and R6 and R7 are hydrogen, represented by compounds of formula (I-1), can generally be prepared by reacting an intermediate of formula (II) with a reagent of formula (III) or a functional derivative thereof, wherein W1 is an appropriate leaving group such as chloro, followed by an intramolecular cyclization which can be performed in a reaction-inert solvent such as xylene and in the presence of a suitable acid, for example acetic acid. The reaction may conveniently be carried out at elevated temperatures ranging from 80xc2x0 C. to reflux temperature. 
Alternatively, compounds of formula (I) wherein xe2x95x90X1xe2x80x94X2xe2x80x94X3 is a trivalent radical of formula (x-1),  greater than Y1xe2x80x94Y2 is a trivalent radical of formula (y4), R9 is hydrogen and R6 and/or R7 are not hydrogen, represented by formula (I-1-a) can be prepared by reacting a compound of formula (IV) with a reagent of formula (V) followed by an intramolecular cyclization which can be performed in a reaction-inert solvent such as ethanol. The reaction may conveniently be carried out at temperatures ranging from room temperature to 80xc2x0 C. 
The compounds of formula (1) wherein xe2x95x90X1xe2x80x94X2xe2x80x94X3 is a trivalent radical of formula (x-2), represented by compounds of formula (I-2), can generally be prepared by reacting a compound of formula (II) with an intermediate of formula (VI). Said reaction can be performed in an appropriate solvent such as 1-butanol at elevated temperatures ranging from 80xc2x0 C. to reflux temperature.
Alternatively, compounds of formula (I-2) can be prepared by reacting a compound of formula (VIII) with an intermediate of formula (VII). Said reaction can be performed in an appropriate solvent such as n-butanol at a temperature ranging between room temperature and reflux temperature. The intermediates of formula (VII) can be prepared by reacting an intermediate of formula (II) with N2H4. Said reaction can be performed in a reaction-inert solvent such as dioxane. The reaction may conveniently be carried out at a temperature ranging between room temperature and 100xc2x0 C. 
Compounds of formula (I-2) wherein R6 is an amine, represented by compounds of formula (I-2-a) can be prepared by reacting an intermediate of formula (VII) with BrCN in a reaction-inert solvent such as methanol. The reaction may conveniently be carried out at a temperature ranging between 0xc2x0 C. and 100xc2x0 C. 
The compounds of formula (I) wherein xe2x95x90X1xe2x80x94X2xe2x80x94X3 is a trivalent radical of formula (x-3), represented by compounds of formula (I-3), can generally be prepared by reacting an intermediate of formula (VII) with a compound of formula (IX) in a reaction-inert solvent such as tetrahydrofuran. The reaction may conveniently be carried out at a temperature ranging between 0xc2x0 C. and 50xc2x0 C.
Alternatively, the compounds of formula (I-3) can be prepared by reacting a compound of formula (X) with an intermediate of formula (II). Said reaction can be performed in an appropriate solvent such as 1-butanol at an elevated temperature ranging from 80xc2x0 C. to reflux temperature. 
The compounds of formula (1) wherein xe2x95x90X1xe2x80x94X2xe2x80x94X3 is a trivalent radical of formula (x-4), represented by compounds of formula (I-4), can generally be prepared by reacting an intermediate of formula (II) with NaN3 in a reaction-inert solvent such as N,N-dimethylformamide. The reaction may conveniently be carried out at an elevated temperature ranging between 60xc2x0 C. and 150xc2x0 C. 
The compounds of formula (I-4) can also be prepared by reacting an intermediate of formula (XVIII) with NaNO2 in an acidic aqueous medium such as, for example HCl in water. 
The compounds of formula (I) wherein xe2x95x90X1xe2x80x94X2xe2x80x94X3 is a trivalent radical of formula (x-9),  greater than Y1xe2x80x94Y2 is a trivalent radical of formula (y-4) and R is hydrogen, represented by compounds of formula (I-5), can generally be prepared by reacting an intermediate of formula (XI) with a compound of formula (XII) in a reaction-inert solvent such as methanol. Convenient reaction temperatures range between room temperature and 80xc2x0 C. The intermediates of formula (XI) can be prepared by reacting an intermediate of formula (XIII) with SeO2 in a reaction-inert solvent such as dioxane. The reaction may conveniently be carried out at an elevated temperature ranging between room temperature and reflux temperature. Intermediates of formula (XIII) can generally be prepared by reacting an intermediate of formula (XIV) with 2-propanone in an acid solution such as a mixture of acetic acid and H2SO4. The reaction may conveniently be carried out at an elevated temperature ranging between room temperature and reflux temperature. 
Compounds of formula (1-6) defined as compounds of formula (1) wherein  greater than Y1xe2x80x94Y2 is a trivalent radical of formula (y-2) or (y4) can be converted to the corresponding compounds of formula (I-7) wherein  greater than Y1xe2x80x94Y2 is a trivalent radical of formula (y-3) or (y-1) and R9 is hydrogen, using art-known reduction procedures such as treatment with NaBH4 or LiAlH 4 in a suitable solvent such as methanol or tetrahydrofuran. 
Conversely, compounds of formula (I-7) can be converted to the corresponding compounds of formula (I-6) by art-known oxidation procedures such as oxidation with MnO2 in a reaction-inert solvent such as dichloromethane.
Also, compounds of formula (I-7) can be converted to compounds of formula (I-7-a) wherein  greater than Y1xe2x80x94Y2 is a trivalent radical of formula (y-3) or (y21) and R9 is other than hydrogen, by reacting these compounds of formula (I-7) with a reagent of formula R9xe2x80x94W2, wherein W2 is an appropriate leaving group such as iodo, in a reaction-inert solvent such as dimethylformnamide and in the presence of NaH. The reaction may conveniently be carried out at a temperature ranging between 0xc2x0 C. and room temperature. 
The compounds of formula (I) wherein R3 is a radical of formula (c-2) and R4 is hydroxy, represented by compounds of formula (I-8) can be converted to compounds of formula (I-8-a) wherein R4 is hydrogen, by submitting the compounds of formula (I-8) to appropriate reducing conditions such as stirring in acetic acid in the presence of formamide. 
Further, compounds of formula (I-8) can be converted to compounds of formula (I-8-b) wherein R4 is halo, by reacting the compounds of formula (I-8) with a suitable halogenating agent such as thionyl chloride or phosphorus tribromide. Successively, the compounds of formula (I-8-b) can be treated with a reagent of formula Hxe2x80x94NR11R12 in a reaction-inert solvent, thereby yielding compounds of formula (I-8-c). 
The intermediates of formula (XV) can be prepared by reacting an intermediate of formula (XV) with a suitable halogenating reagent such as POCl3. 
The intermediates of formula (XV) wherein  greater than Y1xe2x80x94Y2 is of formula (y-1) or (y-4) and R4 is of formula (c-1), can be prepared as described in WO 97/16443 from page 6 line 16 to page 16 line 3.
The intermediates of formula (XV) wherein  greater than Y1xe2x80x94Y2 is of formula (y-1) or (y-4) and R4 is of formula (c-2), can be prepared as described in WO 97/21701 from page 7 line 28 to page 16 line 3.
The intermediates of formula (XV) wherein  greater than Y12xe2x80x94Y2 is of formula (y-2) or (y-3) and R4 is of formula (c-1) or (c-2), can be prepared as described in WO 98/49157 from page 6 line 27 to page 13 line 14.
Alternatively, intermediates of formula (II) wherein W1 is chloro and R3 is hydroxy, represented by intermediates of formula (II-a) can be prepared by reacting an intermediate of formula (XVI), wherein W3 is a suitable leaving group such as Br, with an intermediate ketone of formula (XVII). This reaction is performed by converting the intermediate of formula (XVI) into an organometallic compound, by stirring it with a strong base such as butyl lithium and subsequently adding the intermediate ketone of formula (XVII). The hydroxy derivative can subsequently be converted into other intermediates wherein R4 has another definition by performing art-known functional group transformations. 
Intermediates of formula (IV) can be prepared by reacting an intermediate of formula (XIV) with CH3CN in the presence of NaH and a suitable base such as pyridine. The reaction may conveniently be carried out at an elevated temperature ranging between 50xc2x0 C. and 100xc2x0 C.
Intermediates of formula (XIV) can be prepared according to methods as described in WO 97/16443 and WO 97/21701.
The compounds of formula (I) and some of the intermediates have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration.
The compounds of formula (I) as prepared in the hereinabove described processes are generally racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
The compounds of formula (I), the pharmaceutically acceptable acid addition salts and stereoisomeric forms thereof have valuable pharmacological properties in that they surprisingly have both farnesyl protein transferase (FPTase) and geranylgeranyl transferase (GGTase) inhibitory effects.
Furthermore, the compounds of formula (1), in particular those compounds of formula (I) wherein xe2x95x90X1xe2x80x94X2xe2x80x94X3 is a trivalent radical of formula (x-4), display potent GGTase inhibition.
Other compounds of formula (I) are found to be particularly useful for the inhibition of FPTase activity.
This invention provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of the invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g. loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated ras oncogene; (2) tumor cells in which the ras protein is activated as a result of oncogenic mutation of another gene; (3) benign and malignant cells of other proliferative diseases in which aberrant ras activation occurs. Furthermore, it has been suggested in literature that ras oncogenes not only contribute to the growth of tumors in vivo by a direct effect on tumor cell growth but also indirectly, i.e. by facilitating tumor-induced angiogenesis (Rak. J. et al, Cancer Research, 55, 4575-4580, 1995). Hence, pharmacologically targeting mutant ras oncogenes could conceivably suppress solid tumor growth in vivo, in part, by inhibiting tumor-induced angiogenesis.
This invention also provides a method for inhibiting tumor growth by administering an effective amount of a compound of the present invention, to a subject, e.g. a mammal (and more particularly a human) in need of such treatment. In particular, this invention provides a method for inhibiting the growth of tumors expressing an activated ras oncogene by the administration of an effective amount of the compounds of the present invention. Examples of tumors which may be inhibited, but are not limited to, lung cancer (e.g. adenocarcinoma), pancreatic cancers (e.g. pancreatic carcinoma such as, for example exocrine pancreatic carcinoma), colon cancers (e.g. colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), hematopoietic tumors of lymphoid lineage (e.g. acute lymphocytic leukemia, B-cell lymphoma, Burkitt""s lymphoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), tumors of mesenchymal origin (e.g. fibrosarcomas and rhabdomyosarcomas), melanomas, teratocarcinomas, neuroblastomas, gliomas, benign tumor of the skin (e.g. keratoacanthomas), breast carcinoma, kidney carcinoma, ovary carcinoma, bladder carcinoma and epidermal carcinoma.
This invention may also provide a method for inhibiting proliferative diseases, both benign and malignant, wherein ras proteins are aberrantly activated as a result of oncogenic mutation in genes. With said inhibition being accomplished by the administration of an effective amount of the compounds described herein, to a subject in need of such a treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which ras is activated due to mutation or overexpression of tyrosine kinase oncogenes, may be inhibited by the compounds of this invention.
The compounds of present invention are particularly useful for the treatment of proliferative diseases, both benign and malignant, wherein the K-ras B isoform is activated as a result of oncogenic mutation.
Hence, the present invention discloses the compounds of formula (I) for use as a medicine as well as the use of these compounds of formula (I) for the manufacture of a medicament for treating one or more of the above mentioned conditions.
In view of their useful pharmacological properties, the subject compounds may be formulated into various pharmaceutical forms for administration purposes.
To prepare the pharmaceutical compositions of this invention, an effective amount of a particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, to aid solubility for example, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
Those skilled in the art could easily determine the effective amount from the test results presented hereinafter. In general it is contemplated that an effective amount would be from 0.01 mg/kg to 100 mg/kg body weight, and in particular from 0.05 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.5 to 500 mg, and in particular 1 mg to 200 mg of active ingredient per unit dosage form.